The liver is a critical organ in the human body that is responsible for an array of functions that help support metabolism, immunity, digestion, detoxification, vitamin storage among other functions. It comprises around 2% of an adult’s body weight. The liver is a unique organ due to its dual blood supply from the portal vein (approximately 75%) and the hepatic artery (approximately 25%).
Cellular
The functional unit of the liver is the lobule. Each lobule is hexagonal and a portal triad (portal vein, hepatic artery, bile duct) sits at each corner of the hexagon. The foundation of the lobule is composed of hepatocytes, which have physiologically distinct apical and basolateral membranes. Based on function and perfusion, hepatocytes are divided into 3 zones.
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Zone I – is considered to be the periportal region of hepatocytes and is the best perfused and first to regenerate due to their proximity to oxygenated blood and nutrients. Due to its high perfusion, zone I play a large role in oxidative metabolisms such as beta-oxidation, gluconeogenesis, bile formation, cholesterol formation, and amino acid catabolism.
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Zone II – is defined as the pericentral region of the hepatocytes and zone II sits between zones I and III.
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Zone III – has the lowest perfusion due to its distance from the portal triad. It plays the largest role in detoxification, biotransformation of drugs, ketogenesis, glycolysis, lipogenesis, glycogen synthesis, and glutamine formation.
Bile flow is further facilitated by bile canaliculi, which are formed by apical membranes of neighboring hepatocytes. Due to the 3-dimensional arrangements of hepatocytes, the canaliculi form a lattice-like network or “chicken-wire pattern,” that helps increase the surface area of flow. It is important to recognize that bile and blood flow in opposite directions to each other. This makes sense as the liver produces bile, so bile in the ducts are leaving the liver; whereas, the dual blood supply is entering the liver to perfuse it. Blood drains into the branch of the hepatic vein that lies in the lobule’s center via sinusoidal lumens of the lobule.[rx]
The space between the sinusoidal lumen and the surrounding basolateral membrane of hepatocytes is called the space of Disse. This space is occupied by microvilli extending from the basolateral membrane of the hepatocytes that communicate with the capillary, allowing the hepatocyte to reach its’ blood supply. The space of Disse houses an extracellular matrix composed of a variety of collagens, proteoglycans, and other proteins that help provide scaffolding for the hepatocytes and, by extension, the lobule as a whole. The importance of the scaffolding that takes place in the space of Disse is amplified further by the fact that hepatocytes do not contain a true basement membrane. The space of Disse also contains Kupffer cells (macrophages) and Ito cells (stellate cells). The Kupffer cells sit in the space to filter out unnecessary or pathologic material from the circulation. The Ito cells serve as storage for fat, such as vitamin A. In the right setting, they can also serve as myofibroblasts and aid in the regeneration of the liver.[rx]
The Liver
The liver makes bile, which is essential for the digestion of fats.
Key Points
The liver is a vital organ with a wide range of functions, including detoxification, protein synthesis, and the production of bile, which is necessary for digestion.
The bile produced by the liver is essential for the digestion of fats. Bile is formed in the liver and either stored in the gallbladder or released directly into the small intestine.
Key Terms
- liver: A large organ in the body that stores and metabolizes nutrients, destroys toxins, and produces bile. It is responsible for thousands of biochemical reactions.
- bile: A bitter, brownish-yellow or greenish-yellow secretion produced by the liver, stored in the gallbladder, and discharged into the duodenum, where it aids the process of digestion.
The Role of the Liver
The liver normally weighs between 1.3—3.0 kilograms and is a soft, pinkish-brown organ. It is the second-largest organ in the body, and is located on the right side of the abdomen.
Human liver: Photo of recently removed human liver.
The liver plays a major role in metabolism and has a number of functions in the body, including glycogen storage, plasma protein synthesis, and drug detoxification. It also produces bile, which is important for digestion.
The liver is supplied by two main blood vessels on its right lobe: the hepatic artery and the portal vein. The portal vein brings venous blood from the spleen, pancreas, and small intestine so that the liver can process the nutrients and byproducts of food digestion.
Bile
The bile produced in the liver is essential for the digestion of fats. Bile is formed in the liver, and it is stored in the gallbladder or released directly into the small intestine. After being stored in the gallbladder, the bile becomes more concentrated than when it left the liver; this increases its potency and intensifies its effect in digesting fats.
Anatomy of the Liver
The liver is located in the abdomen and has four lobes.
Key Points
A human liver normally weighs 1.44–1.66 kg (3.2–3.7 lb), and is a soft, pinkish-brown, triangular organ.
The liver is both the largest internal organ (the skin being the largest organ overall) and the largest gland in the human body.
The liver is connected to two large blood vessels: the hepatic artery and the portal vein.
Traditionally, the liver is divided into four lobes: left, right, caudate, and quadrate. The lobes are further divided into lobules, the functional units of the liver.
Each lobule is made up of millions of hepatic cells that are the basic metabolic cells of the liver.
Key Terms
- lobule: A subdivision of the four main liver lobes, the basic functional unit of the liver.
The Liver
The human liver is both the largest internal organ (the skin being the largest organ overall) and the largest gland in the human body. It is a soft, pinkish-brown, triangular organ normally weighing 1.44–1.66 kg (3.2–3.7 lb).
The liver has a wide range of functions including detoxification, protein synthesis, and the production of the biochemicals necessary for digestion. It is located in the right upper quadrant of the abdominal cavity, resting just below the diaphragm. The liver lies to the right of the stomach and overlies the gall bladder.
The position of the liver: The spatial relationship between the liver, stomach, gall bladder, and pancreas. The liver is seen above the stomach, gall bladder, and pancreas.
The liver is connected to two large blood vessels, the hepatic artery, and the portal vein. The hepatic artery carries blood from the aorta to the liver, whereas the portal vein carries blood containing the digested nutrients from the entire gastrointestinal tract, and also from the spleen and pancreas to the liver. These blood vessels subdivide into capillaries that then lead to a lobule.
Lobes of the Liver
Traditionally, the liver is divided into four lobes: left, right, caudate, and quadrate. The lobes are further divided into lobules, the functional units of the liver. Each lobule is made up of millions of hepatic cells that are the basic metabolic cells of the liver.
Histology of the Liver
Hepatocytes are the main tissue cells of the liver. The gallbladder contains the mucosa, muscularis, perimuscular, and serosa layers.
Key Points
A hepatocyte is the main tissue cell of the liver and makes up 70–80% of the liver’s cytoplasmic mass.
Hepatocytes contain large amounts of rough endoplasmic reticulum and free ribosomes.
Hepatocytes are involved in: protein synthesis; protein storage; the transformation of carbohydrates, the synthesis of cholesterol, bile salts, and phospholipids; and detoxification, modification, and excretion of exogenous and endogenous substances.
Hepatocytes are unique in that they are one of the few types of cells in the human body that are capable of regeneration.
There are several different layers of the gallbladder: the mucosa (epithelium and lamina propria), the muscular, the perimuscular, and the serosa.
Key Terms
- hepatocyte: Any of the cells in the liver responsible for the metabolism of proteins, carbohydrates, and lipids, and for detoxification.
The Liver
A hepatocyte is the main tissue cell of the liver and makes up 70–80% of the liver’s cytoplasmic mass. Hepatocytes contain large amounts of rough endoplasmic reticulum and free ribosomes.
- Protein synthesis.
- Protein storage.
- The transformation of carbohydrates.
- The synthesis of cholesterol, bile salts, and phospholipids.
- The detoxification, modification, and excretion of exogenous and endogenous substances.
Hepatocytes also initiate the formation and secretion of bile. Hepatocytes are organized into plates separated by vascular channels (sinusoids) for blood vessels. The hepatocyte plates are one cell thick in mammals.
Hepatocytes are unique in that they are one of the few types of cell in the human body that are capable of regeneration. Hepatocytes are derived from hepatoblasts, the precursor stem cell of the liver that divides to produce new hepatocytes. The liver is capable of complete regeneration from as little as 25% of the original organ.
Blood Supply to the Liver
In the hepatic portal system, the liver receives a dual blood supply from the hepatic portal vein and the hepatic arteries.
Key Points
The hepatic portal vein supplies 75% of the blood to the liver, while the hepatic arteries supply the remaining 25%.
Approximately half of the liver’s oxygen demand is met by the hepatic portal vein, and half is met by the hepatic arteries.
The hepatic portal system connects the capillaries of the gastrointestinal tract with the capillaries in the liver. Nutrient-rich blood leaves the gastrointestinal tract and is first brought to the liver for processing before being sent to the heart.
Key Terms
- hepatic arteries: A blood vessel that supplies oxygenated blood to the liver.
- hepatic portal vein: A vessel located in the abdominal cavity that is formed by the union of the superior mesenteric and splenic veins that channel blood from the gastrointestinal tract and spleen to the capillary beds in the liver.
- cofactors: A substance, especially a coenzyme or a metal, that must be present for an enzyme to function.
In the hepatic portal system, the liver receives a dual blood supply from the hepatic portal vein and hepatic arteries. The hepatic portal vein carries venous blood drained from the spleen, gastrointestinal tract and its associated organs; it supplies approximately 75% of the liver’s blood. The hepatic arteries supply arterial blood to the liver and account for the remainder of its blood flow.
Oxygen is provided from both sources; approximately half of the liver’s oxygen demand is met by the hepatic portal vein, and half is met by the hepatic arteries. Blood flows through the liver tissue and empties into the central vein of each lobule. The central veins coalesce into hepatic veins that collect the blood leaving the liver and bring it to the heart.
Hepatic veins: An image of a liver with the hepatic veins labeled. They are located in the inferior vena cava.
A portal system is a venous structure that enables blood from one set of capillary beds to drain into another set of capillary beds, without first returning this blood to the heart. The majority of capillaries in the body drain directly into the heart, so portal systems are unusual.
The hepatic portal system connects the capillaries of the gastrointestinal tract with the capillaries in the liver. Nutrient-rich blood leaves the gastrointestinal tract and is first brought to the liver for processing before being sent to the heart. Here, carbohydrates and amino acids can be stored or used to make new proteins and carbohydrates.
The liver also removes vitamins and cofactors from the blood for storage, as well as filters any toxins that may have been absorbed along with the food. When any of these stored substances are needed, the liver releases them back into circulation through the hepatic veins.
Hepatic portal circulation: A diagram that shows the hepatic portal vein and its territory.
Liver Function
The liver is thought to be responsible for up to 500 separate functions.
Key Points
The liver is thought to be responsible for up to 500 separate functions, usually in combination with other systems and organs.
The various functions of the liver are carried out by the liver cells or hepatocytes.
Excessive alcohol consumption can cause liver disease.
The liver tissue of an alcoholic may become clogged with fats and adversely affect liver function.
Key Terms
- liver disease: Also called hepatic disease, this is an umbrella term referring to damage to or disease of the liver.
- IGF: A hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin is used for the treatment of growth failure.
Functions of the Liver
The human liver is thought to be responsible for up to 500 separate functions, usually in combination with other systems and organs. The various functions of the liver are carried out by the liver cells or hepatocytes. Currently, there is no artificial organ or device capable of emulating all the functions of the liver.
The liver: The liver, or hepar, is a vital organ present in vertebrates and some other animals. It has a wide range of functions including detoxification, protein synthesis, and the production of the biochemicals necessary for digestion.
The liver is the mainstay of protein metabolism— it synthesizes as well as degrades. It performs several roles in carbohydrate and lipid metabolism. The bulk of the lipoproteins are synthesized in the liver.
Liver tissue of an alcoholic: A healthy liver can break down alcohol. However, the overstressed liver of an alcoholic may become clogged with fats that adversely affect liver function. This type of tissue is most common in alcoholic hepatitis (a prevalence of 65%) and alcoholic cirrhosis (a prevalence of 51%).
In the first- trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task.
The liver also produces the insulin-like growth factor 1 (IGF-1), a polypeptide protein hormone that plays an important role in childhood growth and continues to have anabolic effects in adults.
The liver stores a multitude of substances, including glucose (in the form of glycogen), vitamin A (1–2 years’ supply), vitamin D (1–4 months’ supply), vitamin B12 (1–3 years’ supply), iron, and copper. The liver is responsible for immunological effects, acting as a sieve for the antigens that are carried to it via the portal system.
The liver synthesizes angiotensinogen, a hormone that is responsible for raising blood pressure when the angiotensinogen is activated by renin, an enzyme that is released when the kidney senses low blood pressure.
The liver breaks down or modifies toxic substances, such as alcohol and most medicinal products, in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor.
Preferably, the toxins are conjugated to avail excretion in bile or urine. The liver breaks down insulin and other hormones.
Bile Production
Bile is a fluid produced by the liver that aids the process of digestion and the absorption of lipids in the small intestine.
Key Points
Bile is a composition of the following materials: water (85%), bile salts (10%), mucus and pigments (3%), fats (1%), inorganic salts (0.7%), and cholesterol (0.3%).
Bile can either drain directly into the duodenum or be temporarily stored in the gallbladder.
Bile, which is alkaline, also has the function of neutralizing any excess stomach acid in the small intestine.
Key Terms
- bile: A bitter, brownish-yellow or greenish-yellow secretion produced by the liver, stored in the gallbladder, and discharged into the duodenum, where it aids the process of digestion.
Bile: Micrograph of bile (yellow material) in a liver biopsy.
Bile, or gall, is a bitter-tasting, dark-green to yellowish-brown fluid produced by the liver that aids the process of digestion of lipids in the small intestine. Bile is stored in the gallbladder, and upon eating is discharged into the duodenum through the bile duct. Bile is a composition of the following materials: water (85%), bile salts (10%), mucus and pigments (3%), fats (1%), inorganic salts (0.7%), and cholesterol (0.3%).
Bile acts as a surfactant, helping to emulsify the fats in the food, in the same way, that soap emulsifies fat. The bile salts are ionically charged, with a hydrophobic end and a hydrophilic end.
When exposed to water mixed with fat, such as in the small intestine, the bile salts congregate around a fat droplet with their hydrophobic side pointing towards the fat and their hydrophilic side pointing towards the water. This increases the surface area of the fat and allows greater access by the pancreatic enzymes that break down fats.
Since bile increases the absorption of fats, it is an important part of the absorption of fat-soluble vitamins, such as the vitamins D, E, K, and A.
Besides its digestive function, bile serves also as the route of excretion for bilirubin, a waste byproduct of red blood cells that is recycled by the liver. The alkaline bile also has the function of neutralizing any excess stomach acid before it enters the ileum, the final section of the small intestine.
Bile salts also act as bactericides, destroying many of the microbes that may be present in the food.
Bile salt action on lipids: Bile salts congregate around fat and separate them into small droplets called micelles.
Bile is an important fluid as it helps excrete material not excreted by the kidneys and aids in the absorption and digestion of lipids via secretion of bile salts and acids. Bile is produced by hepatocytes and is mainly composed of water, electrolytes, bile salts, bile acids, cholesterol, bile pigment, bilirubin, and phospholipids in addition to other substances. Bile is secreted from hepatocytes into the bile canaliculi where it travels from smaller ducts to the larger ducts eventually ending up in the duodenum or being stored in the gallbladder for storage and concentration as determined by the duct and sphincter of Oddi pressures. Following secretion of bile into the duodenum, it undergoes enterohepatic circulation, where it performs its job in the bowel, and bile components that are not excreted are recycled by conversion into bile acids by gut bacteria for reuse by absorption in the ileum and transport back to the liver.
Fat-Soluble Vitamin Storage and/or Metabolism
Most fat-soluble vitamins reach the liver via intestinal absorption in the form of chylomicrons or VLDL. The liver stores and/or metabolizes fat-soluble vitamins. As discussed earlier, vitamin A is stored in Ito cells. It can undergo oxidation into retinal followed by retinoic acid for phototransduction, or retinoic acid can be conjugated into glucuronide for secretion into bile. Whether vitamin D3 comes from the skin, animal products, or plant products, it must undergo 25-hydroxylation by the hepatic CYP-450 system, which is further hydroxylated in the kidney to achieve its functional form. The hepatic CYP-450 system then hydroxylates carbon 24 to render vitamin D inactive. The liver receives vitamin E in its alpha and gamma-tocopherol forms. Alpha-tocopherol is integrated with VLDL or HDL in the liver and is then secreted back into circulation while the liver metabolizes the gamma-tocopherol form for excretion. While vitamin K is not stored or metabolized in the liver, its presence is essential as the liver enzyme, gamma-glutamyl carboxylase requires it for gamma-carboxylation of coagulation factors II, VII, IX, X, and protein C and protein S.
Drug Metabolism
Another critical function of the liver is metabolism and/or detoxification of xenobiotics. The liver uses lysosomes for some of these substances, but a major route of metabolism and detoxification is through biotransformation. The liver functions to transform xenobiotics mainly by converting them from a lipophilic form to a hydrophilic form through 2 reactions: phase I and phase II. These reactions mainly take place in the smooth endoplasmic reticulum of hepatocytes. Phase I reactions create a more hydrophilic solute via oxidation, reduction, and hydrolysis using primarily the cytochrome P450 (CYP450) family of enzymes. The product of phase I has an oxygen species that reacts better with enzymes involved with phase II reactions. Phase II reactions conjugate the metabolites created in phase I to make them more hydrophilic for secretion into blood or bile. There are three main avenues for conjugation performed in phase II reactions: conjugation to glucuronate, glutathione, or sulfate. Conjugation to glucuronate, such as with bilirubin, takes place in the smooth endoplasmic reticulum. Substances undergoing sulfate conjugation, such as alcohols, are usually done in the cytosol due to the location of the needed enzymes. Most glutathione conjugation occurs in the cytosol, with a minority occurring in the mitochondria. It is essential that glutathione is reduced and depletion of reduced glutathione for conjugation can allow the buildup of toxic metabolites as seen in acetaminophen overdose. Some describe the transport of metabolites produced from these reactions as phase III. Other organs, such as the kidney and gut can aid in drug metabolism. Multiple factors such as age, gender, drug-drug interactions, diabetes, pregnancy, liver or kidney disease, inflammation, or genetics to name a few, affect drug metabolism. [rx]
Bilirubin Metabolism
The liver plays a significant role in the breakdown of heme. Hemolysis takes place in multiple locations throughout the body, including the liver, spleen, and bone marrow. Heme is broken down into biliverdin, which is then reduced to unconjugated bilirubin. The liver receives unconjugated bilirubin bound to albumin from the circulation. The unconjugated bilirubin then undergoes conjugation via the uridine diphosphate glucuronyltransferase (UGT) system, a phase II process, to become hydrophilic. The newly conjugated bilirubin then is secreted via bile canaliculi into the bile or small amounts dissolve in the blood where it then gets filtered for excretion by the kidneys. Most conjugated bilirubin enters the bile and is excreted with bile in feces as it is not absorbable by the intestinal wall. Some bilirubin is converted to urobilinogen or unconjugated bilirubin by gut bacteria for reabsorption to undergo enterohepatic circulation.[rx][rx]
Other Functions
The liver plays a role in thyroid hormone function as the site of deiodination of T4 to T3. The liver manages the synthesis of nearly every plasma protein in the body, some examples include albumin, binding globulins, protein C, protein S, and all the clotting factors of the intrinsic and extrinsic pathways besides factor VIII.
References
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